Cyclohepta[b]indoles (1) exhibit a broad spectrum of biological activity. For instance, compound 2 is a potent inhibitor (IC50=63 nM) of SIRT1, a member of the class III histone deacetylases (HDAC; Napper, et al. (2005) J. Med. Chem. 48:8045). SIRT1 can effectively deacetylate p53 and has also been implicated in the regulation of apoptosis. With an IC50 of 100 nM, compound 3 inhibits the production of leukotriene B4 (LTB4), which is involved in various inflammatory responses (Kuehm-Caubère, et al. (1999) Eur. J. Med. Chem. 34:51). A third molecule, compound 4, inhibits adipocyte fatty-acid binding protein (A-FABP) with an IC50 of 450 nM (Barf, et al. (2009) Bioorg. Med. Chem. Lett. 19:1745).

The biology of cyclohepta[b]indoles, as well as cyclopenta- and cyclohexa[b]indoles, has attracted considerable interest from the pharmaceutical industry as potential therapeutics. In this respect, various compounds with this structural motif have been described. See, e.g., WO 2010/036998, US 2011/0152306, US 2009/0170923, US 2009/0156621, WO 2004/063156, WO 2010/054382, WO 2006/047017, WO 2006/034090, WO 2004/069831, EP 1184373, WO 2009/120720, WO 2005/023245, WO 2004/110999, WO 2005/094833, WO 03/091257, US 2008/0027090, WO 2011/044134, US 2011/0003737, WO 2010/111483, US 2007/0037791, EP 1505061, WO 2006/055760 and WO 2008/021364.
The preparation of cycloalka[b]indoles often includes the Fisher indole synthesis which, while quite useful, possesses certain limitations (Ambekar (1983) Curr. Sci. 52:578; Robinson (1969) Chem. Rev. 69:227; Inman & Moody (2011) Chem. Commun. 47:788). These include the need to make the requisite hydrazine and ketone starting materials. Regioselectivity with unsymmetrical ketones can also be problematic. Finally, electron-withdrawing groups on the aromatic hydrazine can substantially attenuate reactivity. Other methods for preparing cycloalka[b]indoles are known but have not been extensively explored (Willis, et al. (2005) Angew. Chem. Int. Ed. 44:403; Barluenga, et al. (2007) Angew. Chem. Int. Ed. 46:1529; Sun, et al. (2011) Angew. Chem. Int. Ed. 50:1702; Liu & Widenhoefer (2004) J. Am. Chem. Soc. 126:10250; Ragains & Winkler (2006) Org. Lett. 8:4437; Silvanus, et al. (2009) Org. Lett. 11:1175; Ishikura & Kato (2002) Tetrahedron 58:9827).
(4+3) Cycloaddition reactions have been explored in some detail (Harmata (2010) Chem. Comm. 46:8886; Harmata (2001) Acc. Chem. Res. 34:595; Harmata (2006) Adv. Synth. Catal. 348:2297; Battiste, et al. (2006) Chem. Eur. J. 12:3438; Hartung & Hoffman (2004) Angew. Chem., Int. Ed. 43:1934; Harmata (1997) Tetrahedron 53:6235; Chung, et al. (2009) J. Am. Chem. Soc. 131:4556; Harmata, et al. (1996) J. Am. Chem. Soc. 118:2860; Nilson & Funk (2011) J. Am. Chem. Soc. 133:12451; Yu, et al. (2010) Org. Lett. 12:5135; Liu & Chiu (2011) Chem. Commun. 47:3416; Lee, et al. (1998) J. Org. Chem. 63:2804; Lee & Cha (2000) Tetahedron 56:10175; Davies & Dai (2004) J. Am. Chem. Soc. 126:2692). A stabilizing group is usually present at C2 of the 2π component (Scheme 1).

Heteroatom substitution with sulfur, oxygen, and halide at the terminal ends of the allylic cation are known (Xiong, et al. (2003) J. Am. Chem. Soc. 125:12694; Lohse & Hsung (2011) Chem. Eur. J. 17:3812; Lohse, et al. (2011) J. Org. Chem. 76:3246; Harmata (2010) Chem. Commun. 46:8904; Jeffrey, et al. (2011) J. Am. Chem. Soc. 133:7688; Lee & Cha (2001) J. Am. Chem. Soc. 123:3243; Aungst, Jr. & Funk (2001) Org. Lett. 3:3553; Harmata & Wacharasindhu (2005) Org. Lett. 7:2563; Lee & Cha (1999) Org. Lett. 1:523; Blackburn, et al. (1983) Can. J. Chem. 61:1981; Harmata, et al. (2004) Heterocycles 62:583; Harmata & Gamlath (1988) J. Org. Chem. 53:6154; Hardinger, et al. (1995) J. Org. Chem. 60:1104; Sasaki, et al. (1982) Tetrahedron Lett. 23:1693). However, cycloaddition reactions utilizing substrates with nitrogen-based substituents have are rare (Xiong, et al. (2003) J. Am. Chem. Soc. 125:12694; Lohse & Hsung (2011) Chem. Eur. 17:3812; Lohse, et al. (2011) J. Org. Chem. 76:3246).